Recent years have seen a great flourishing of aquiculture (culture of saltwater fish and freshwater fish) with the attendant outbreaks of various fish diseases. For the prevention and treatment of such fish diseases, taking pseudotuberculosis in yellowtail as an example, antibacterial agents such as ampicillin, oxolinic acid and the like are frequently employed. However, the common usage of these antibacterial agents is presenting the problem that pathogenic bacteria resistant to these antibacterial agents have emerged with increasing frequencies.
There exists, therefore, a true need for development of new antibacterial agents for the prevention and therapy of fish diseases, which do not have cross resistance with the conventional drugs and are active against such resistant microorganisms.
To resolve this problem, the inventors of the present invention contemplated the use of bicozamycin [the same substance as WS-4545 substance which is produced by certain microorganisms of the genus Streptomyces (Japanese Publication of Examined Patent Application No. 29158/1973)] but found that this substance was not satisfactory in the absorption from the intestinal tract.
Meanwhile, certain esters synthesized for improving the absorption of bicozamycin after oral administration [the same substances as acylated WS-4545 substance (Japanese Publication of Unexamined Patent Application No. 39497 (1973)] fulfilled the need (The Journal of Antibiotics Vol. XXV, No. 10, pp. 576-581) but application of such bicozamycin esters to fish has been refrained from for the following reason. Thus, drugs for fish are usually administered as incorporated in a raw fish mince but it was generally suspected that if an ester of bicozamycin be administered to fish, especially yellowtail, in this manner, the ester would be hydrolyzed back to bicozamycin by the esterase occurring in the fish mince so that the object of improving the oral absorption of the drug would not be accomplished. (Actually, when a known ester of ampicillin, viz. bacampicillin, is incorporated in a fish mince before administration, it is decomposed in the mince).
Under the circumstances, the inventors of the present invention dared to experimentally administer a bicozamycin ester [compound (I)] to fish in the above manner and found surprisingly that the ester was not substantially decomposed in the fish mince but was well absorbed and retained in high concentrations for long in the fish blood. The finding was followed by further research which has culminated in the present invention.